The purpose of this work is to evaluate drug therapy in chronic pain syndromes that are considered resistant to known approaches such as pain caused by nerve injury and by advanced cancer. The first study in this series has shown that amitriptyline relieves diabetic neuropathy pain in patients with normal as well as depressed mood. Twenty-nine patients received 6 weeks of amitriptyline (25-150 mg at bedtime, to maximum tolerated) and 6 weeks of a placebo chosen to mimic amitriptyline side-effects, in a crossover design. Patients' global evaluations after treatment periods indicated that 23 had less pain with amitriptyline, 1 had less pain with placebo, and 5 had similar levels of pain with the two drugs. Amitriptyline was more analgesic than placebo in both the 15 non-depressed patients and in the 14 depressed patients. We conclude that amitriptyline has an analgesic action in diabetic neuropathy that is independet of its antidepressant effects. In 409 patients with post-herpetic neuralgia, a comparison of single doses of clonidine, codeine, and ibuprofen to placebo did not demonstrate a specific analgesic effect for any drug. It was shown that with drug or placebo, patients report more pain relief when they detect side-effects, which has implications for analgesic trial design and clinical treatment. Thirty-two of a projected 40 post-herpetic neuralgia patients have completed a study of chronic amitriptyline vs. lorazepam vs. placebo; an interim analysis showed that amitriptyline was a superior analgesic to the other two treatments. A study of the delta opiate agonist metkephamid in cancer patients with varying degrees of tolerance at the mu or morphine receptor was suspended because of drug side-effects. Resumption awaits the availability of other investigational delta or kappa receptor opiates.